A comparison of the criterion validity of popular measures of narcissism and narcissistic personality disorder via the use of expert ratings.
The growing interest in the study of narcissism has resulted in the development of a number of assessment instruments that manifest only modest to moderate convergence. The present studies adjudicate among these measures with regard to criterion validity. In the 1st study, we compared multiple narcissism measures to expert consensus ratings of the personality traits associated with narcissistic personality disorder (NPD; Study 1; N = 98 community participants receiving psychological/psychiatric treatment) according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) using 5-factor model traits as well as the traits associated with the pathological trait model according to the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; American Psychiatric Association, 2013). In Study 2 (N = 274 undergraduates), we tested the criterion validity of an even larger set of narcissism instruments by examining their relations with measures of general and pathological personality, as well as psychopathology, and compared the resultant correlations to the correlations expected by experts for measures of grandiose and vulnerable narcissism. Across studies, the grandiose dimensions from the Five-Factor Narcissism Inventory (FFNI; Glover, Miller, Lynam, Crego, & Widiger, 2012) and the Narcissistic Personality Inventory (Raskin & Terry, 1988) provided the strongest match to expert ratings of DSM-IV-TR NPD and grandiose narcissism, whereas the vulnerable dimensions of the FFNI and the Pathological Narcissism Inventory (Pincus et al., 2009), as well as the Hypersensitive Narcissism Scale (Hendin & Cheek, 1997), provided the best match to expert ratings of vulnerable narcissism. These results should help guide researchers toward the selection of narcissism instruments that are most well suited to capturing different aspects of narcissism.


Tension-free polypropylene mesh-related surgical repair for pelvic organ prolapse has a good anatomic success rate but a high risk of complications.
Food and Drug Administration announcements have highlighted the standard rate of mesh-related complications. We aimed to report the short-term results and complications of tension-free polypropylene mesh (PROSIMA™) surgical repair of pelvic organ prolapse (POP) using the standard category (C), timing (T), and site (S) classification system. A prospective cohort study of 48 patients who underwent PROSIMA™ mesh kit-related surgical repairs were followed for two years at Peking Union Medical College Hospital. Recurrence was defined as symptomatic POP quantification (POP-Q) Stage II or higher (leading edge ≥ -1 cm). The Patient Global Impression of Change Questionnaire, the Chinese version of the Pelvic Floor Impact Questionnaire short-form-7 and POP/Urinary Incontinence Sexual Questionnaire short-form-12 were used to evaluate the self-perception and sexual function of each patient. Mesh-related complications conformed to the International Urogynecological Association/International Continence Society joint terminology. The paired-sample t-test, one-way analysis of variance, Fisher's exact test, Kaplan-Meier survival analysis and log-rank test were used to analyze data. All patients were followed up for ≥12 months; 30 (62.5%) patients completed the 24 months study. We observed a 93.8% (45/48) positive anatomical outcome rate at 12 months and 90.0% (27/30) at 24 months. Recurrence most frequently involved the anterior compartment (P < 0.05). Pelvic symptoms improved significantly from baseline (P < 0.05), although the patients' impressions of change and sexual function were not satisfying. Vaginal complication was the main complication observed (35.4%, 17/48). The survival analysis did not identify any relationship between vaginal complication and anatomical recurrent prolapse (POP-Q ≥ Stage II) (P = 0.653). Tension-free polypropylene mesh (PROSIMA™ )-related surgical repair of POP has better short-term anatomical outcomes at the apical and posterior compartments, but a low patient satisfaction rate. The mesh complications were not the definitive cause of recurrence.


Blood transfusions and the subsequent risk of hematologic malignancies.
Blood transfusions are associated with viral transmission and immunomodulation, perhaps increasing subsequent risk of hematologic malignancies (HMs). Prior studies of transfusion recipients have lacked details on specific HM subtypes. Risk of HM after blood transfusion was evaluated in a US population-based case-control study (77,488 elderly HM cases identified through cancer registries, 154,509 controls). Transfusions were identified using linked Medicare hospitalization claims. Polytomous logistic regression was used to calculate odds ratios (ORs) associating transfusion and HM subtypes by features suggestive of a causal relationship. A history of transfusion was present in 7.9% of HM cases versus 5.9% of controls. Associations for most HM subtypes suggested reverse causality: ORs were elevated only during the shortest latency periods; ORs for unspecified anemia and gastrointestinal bleeding, which may be related to undiagnosed HM, were stronger than for surgeries, which are unlikely to be related to HM; and/or there was no dose response. In contrast, risk for lymphoplasmacytic lymphoma (1397 cases) was elevated at long latency (OR, 1.56 at 10+ years after transfusion), after transfusions related to surgeries (OR, 1.22-1.47), and in a dose-response relationship with number of transfusion-related hospitalizations (OR, 1.53 with one hospitalization; OR, 1.80 with two or more hospitalizations, p trend < 0.0001). Risk for marginal zone lymphoma (1915 cases) was also elevated at 10+ years after transfusion (OR, 1.80). Consistent with prior studies, blood transfusions did not increase risk of most HM subtypes. Patterns of elevated risk for lymphoplasmacytic and marginal zone lymphomas suggest an etiologic role for transfusion.


Lipidated promiscuous peptide augments the expression of MHC-II molecules on dendritic cells and activates T cells.
In spite of the fact that BCG is the most widely used vaccine, tuberculosis (TB) continues to be a major killer disease in TB-endemic regions. Recently, many emerging evidences from the published literature indicate the role of environmental mycobacteria in blocking the processing and presentation of BCG antigens and thereby impairing with suboptimal generation of protective T cells. To surmount this problem associated with BCG, we constructed a novel lipopeptide (L91) by conjugating a promiscuous peptide consisting of CD4 + T-helper epitope of sequence of 91-110 of 16 kDa antigen of Mycobacterium tuberculosis to Pam2Cys, an agonist of Toll-like receptor-2. Mice were immunized subcutaneously with 20 nmol of L91, followed by a booster with 10 nmol, after an interval of 21 days of primary immunization. Animals were sacrificed after seven days of post-booster immunization. L91 induced immune response was characterized by the expression of MHC-II and CD74 on the surface of dendritic cells (DCs) by flowcytometry. Cytokines (IL-4, IL-10, IFN-γ) secretion and anti-peptide antibodies were measured by ELISA. Self-adjuvanting lipopeptide vaccine (L91) was directly bound to MHC-II molecules and without requiring extensive processing for its presentation to T cells. It stimulated and activated dendritic cells and augmented the expression of MHC-II molecules. Further, it activated effector CD4 T cells to mainly secrete interferon (IFN)-γ but not interleukin (IL)-4 and IL-10. L91 did not elicit anti-peptide antibodies. The findings suggest that L91 evokes maturation and upregulation of MHC class II molecules and promotes better antigen presentation and, therefore, optimum activation of T cells. L91 mainly induces effector Th1 cells, as evidenced by predominant release of IFN-γ, consequently can mount favourable immune response against M. tuberculosis . As L91 does not provoke the generation of anti-peptide antibodies, there is no fear of the efficacy of the vaccine being neutralized by pre-existing anti-mycobacterial antibodies in TB-endemic population. In conclusion, L91 may be considered as a future potential candidate vaccine against TB.


Oculopharyngeal muscular dystrophy (OPMD) and dementia in a 75-year-old female.
Oculopharyngeal muscular dystrophy (OPMD) is a relatively rare, adult-onset disorder characterised by proximal limb weakness, progressive eyelid drooping and swallowing difficulties. Preliminary research suggests there could be a link between OPMD and dementia; however, the current literature is relatively limited and inconsistent. This case study describes a 75-year-old female with OPMD, presenting to an older adults community mental health team with memory problems and word finding difficulties. A neuropsychological assessment was carried out. The results of her assessment were difficult to interpret; she demonstrated impairments in most cognitive domains tested and her presentation did not appear to reflect any typical dementia profile. It was thought she was most likely presenting with a dementia; however, the exact aetiology remains unclear. The dementia could be a result of OPMD, vascular changes or both. This report emphasises the need for further research into the possible causal link between OPMD and dementia/cognitive decline.


Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors.
Metformin is a widely used antidiabetic drug, and epidemiology studies for pancreatic and other cancers indicate that metformin exhibits both chemopreventive and chemotherapeutic activities. Several metformin-induced responses and genes are similar to those observed after knockdown of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 by RNA interference, and we hypothesized that the mechanism of action of metformin in pancreatic cancer cells was due, in part, to downregulation of Sp transcription factors. Treatment of Panc1, L3.6pL and Panc28 pancreatic cancer cells with metformin downregulated Sp1, Sp3 and Sp4 proteins and several pro-oncogenic Sp-regulated genes including bcl-2, survivin, cyclin D1, vascular endothelial growth factor and its receptor, and fatty acid synthase. Metformin induced proteasome-dependent degradation of Sps in L3.6pL and Panc28 cells, whereas in Panc1 cells metformin decreased microRNA-27a and induced the Sp repressor, ZBTB10, and disruption of miR-27a:ZBTB10 by metformin was phosphatase dependent. Metformin also inhibited pancreatic tumor growth and downregulated Sp1, Sp3 and Sp4 in tumors in an orthotopic model where L3.6pL cells were injected directly into the pancreas. The results demonstrate for the first time that the anticancer activities of metformin are also due, in part, to downregulation of Sp transcription factors and Sp-regulated genes.


Validation of the reflux disease questionnaire for an Italian population of patients with gastroesophageal reflux disease.
The reflux disease questionnaire (RDQ) is a very simple questionnaire based on only 12 questions that can be answered and evaluated quickly in a primary care setting, which was already found to be valid and reliable in the diagnosis of gastroesophageal reflux disease (GERD). As an English and a German version of the RDQ exist, but not an Italian one, we aimed at translating the RDQ into Italian and evaluating its reliability for the use of Italian-speaking GERD patients. For the purpose of linguistic validation, we translated backward and forward the original RDQ into Italian and again into English. For the purpose of assessing internal consistency, test-retest, and interrater reliability, 130 GERD patients were used, of whom 57 patients had an endoscopic oesophagitis of grade A to C according to the Los Angeles classification and 63 patients had uninvestigated GERD symptoms but with a frequency of heartburn and/or regurgitation at least twice a week. After professional translation, the Italian RDQ was judged to retain fully the meaning of the original RDQ. Internal consistency, as judged by the (Cronbach's alpha) was satisfactory, with an overall RDQ scale alpha=0.86 (minimum acceptable value=0.70). Test--retest reliability (Spearman coefficient) was again found to be optimal, with individual item values ranging between 0.74 (for 'pain in the upper stomach: frequency') and 0.90 (for 'burning feeling behind breastbone: severity'). Finally, the correlation coefficient was 0.96 for the total scale and a range of 0.85-0.98 for individual items, indicating extremely satisfactory concordance. The Italian RDQ appears to be a simple, reproducible, and reliable tool for the diagnosis of GERD. We believe that this questionnaire is well suited for use, both in primary care settings and in epidemiological studies, in particular for the assessment of so-called typical symptoms.


Sensitivity of KATP channels to cellular metabolic disorders and the underlying structural basis.
ATP-sensitive potassium (KATP) channels formed by a combination of SUR/Kir6.x subunits play a crucial role in protection against hypoxic or ischemic injuries resulting from cell metabolic disorders. In this study we investigated the effects of Na-azide, a metabolic inhibitor, on KATP channels expressed in Xenopus oocytes, and explored the structure basis for their sensitivity to cell metabolic disorders. Six subtypes of KATP channels (wild SUR1/Kir6.2, SUR2B/Kir6.2, SUR1/Kir6.1, SUR2B/Kir6.1, SUR2A/Kir6.2 and SUR2A/Kir6.1), as well as eleven subtypes of KATP channels with mutant subunits were expressed in Xenopus oocytes. KATP currents were recorded using a two-electrode voltage clamp recording technique. The drugs were applied through bath. Except SUR2A/Kir6.1, five subtypes of KATP channels were activated by Na-azide (3 mmol/L) with an order of the responses: SUR1/Kir6.2>SUR2B/Kir6.2>SUR1/Kir6.1>SUR2B/Kir6.1>SUR2A/Kir6.2, and the opening rate (t1/2) was SUR1/Kir6.x>SUR2B/Kir6.x>SUR2A/Kir6.2. Furthermore, Kir6.2, rather than Kir6.1, had intrinsic sensitivity to Na-azide, and the residues involved in ATP-binding (R50 and K185) or pH-sensing (H175) were associated with the sensitivity of the Kir6.2 subunit to Na-azide. Moreover, the residues (K707 and K1348) within the Walker A (WA) motifs of two nucleotide-binding domains (NBDs) were essential for SUR2B/Kir6.x (especially SUR2B/Kir6.1) channel activation by Na-azide, suggesting a key role for Mg-adenine nucleotide binding and/or hydrolysis in the SUR2B subunit. Among the six subtypes of KATP channels, SUR1/Kir6.2 is the most sensitive, whereas SUR2A/Kir6.1 is insensitive, to cell metabolic disorders. The Kir6.2 subunit, rather than the Kir6.1 subunit, has intrinsic sensitivity to cell metabolic disorders. The residues (K707 and K1348) within the WA motifs of SUR2B are important for the sensitivity of SUR2B/Kir6.x channels to cell metabolic disorders.


[Factors associated with job satisfaction in home care nurses].
Although there have been articles written in the literature on nurse job satisfaction, a national study addressing the job satisfaction of home care nurses in Taiwan has never been performed before. The purpose of this study was to investigate home care nurse job satisfaction in Taiwan and correlated factors. A cross-sectional approach was used to survey participants, who comprised clinical home care nurses currently working in public / private hospitals or independent healthcare institutions in Taiwan. Qualified nurses in the potential study sample were first contacted by phone, and structured questionnaires were delivered by post. A total of 365 questionnaires were sent, with 337 questionnaires returned. Overall job satisfaction for the study subjects was 67.74%, with the subscale "satisfaction with the job itself" scoring the highest and the subscale "satisfaction with supervisors" scoring the lowest among the five job satisfaction subscales. Linear regression analysis demonstrated that those who had served as home nursing practicum course instructors, were over 35-years of age or had higher perceived job complexity tended to have higher job satisfaction. Higher work pressure was associated with less job satisfaction. Those who received 10-20 hours of continuing education had a higher average job satisfaction than those who received continuing education for either more than 20 hours or less than 10 hours. Those nurses who had higher work values and were currently married demonstrated higher job satisfaction. These seven factors explained 49.7% of total variance. Study results may serve as reference for institutions to help promote higher job satisfaction in home care nurses. Home care nurse job satisfaction may be improved by providing an appropriate number of hours of continuing education and implementing a nurse advancement system in home care in order to increase intrinsic work value.


STACKing the odds for adolescent survival: health service factors associated with full retention in care and adherence amongst adolescents living with HIV in South Africa.
There are two million HIV-positive adolescents in southern Africa, and this group has low retention in care and high mortality. There is almost no evidence to identify which healthcare factors can improve adolescent self-reported retention. This study examines factors associated with retention amongst antiretroviral therapy (ART)-initiated adolescents in South Africa. We collected clinical records and detailed standardized interviews (n = 1059) with all 10- to 19 year-olds ever initiated on ART in all 53 government clinics of a health subdistrict, and community traced to include lost-to-follow-up (90.1% of eligible adolescents interviewed). Associations between full self-reported retention in care (no past-year missed appointments and 85% past-week adherence) and health service factors were tested simultaneously in sequential multivariate regression and marginal effects modelling, controlling for covariates of age, gender, urban/rural location, formal/informal housing, maternal and paternal orphanhood, vertical/horizontal HIV infection, overall health, length of time on ART and type of healthcare facility. About 56% of adolescents had self-reported retention in care, validated against lower detectable viral load (AOR: 0.63, CI: 0.45 to 0.87, p = 0.005). Independent of covariates, five factors (STACK) were associated with improved retention: clinics Stocked with medication (OR: 3.0, CI: 1.6 to 5.5); staff with Time for adolescents (OR: 2.7, CI: 1.8 to 4.1); adolescents Accompanied to the clinic (OR: 2.3, CI: 1.5 to 3.6); enough Cash to get to clinic safely (OR: 1.4, CI: 1.1 to 1.9); and staff who are Kind (OR: 2.6, CI: 1.8 to 3.6). With none of these factors, 3.3% of adolescents reported retention. With all five factors, 69.5% reported retention. This study identifies key intervention points for adolescent retention in HIV care. A basic package of clinic and community services has the potential to STACK the odds for health and survival for HIV-positive adolescents.


An oral care self-management support protocol (OrCaSS) to reduce oral mucositis in hospitalized patients with acute myeloid leukemia and allogeneic hematopoietic stem cell transplantation: a randomized controlled pilot study.
Oral mucositis (OM) is a common and debilitating side effect of chemoradiotherapy in patients awaiting allogeneic hematopoietic stem cell transplantation (aHSCT). The aim of this pilot RCT was to compare an oral care self-management support protocol (OrCaSS) to usual pre-aHSCT care. Feasibility was tested, effect sizes calculated for OM (primary outcome), and patient adherence was measured (secondary outcome). Eighteen AML patients awaiting aHSCT and hospitalized between August 2012 and April 2013 were randomized 1:1 to usual care (UCG) and intervention (IG) groups. The OrCaSS protocol consisted of two sessions of educational and behavioral interventions, the first delivered 1 week pre-admission (T1), the second on admission day (T2). Via field notes, practicability and acceptability were evaluated to explore the feasibility of intervention and study procedures. OM data were collected at T1, T2, and daily for 28 days using the WHO scale. The effect size r was calculated (r less than -0.1 ≙ small and greater than or equal to -0.3 ≙ medium). Patients' adherence to the protocol was assessed at T1, T2, and 8-10 days post-HSCT (T3). Research and intervention procedures were feasible. OM incidence was 100 %. The IG's median highest OM grade was 2.0 (IQR = 2); the UCGs was 3.0 (IQR = 2; r = -0.1). Median OM durations were 12 days in the IG and 14 days in the UCG (r = -0.1). OM onset was 2 days later in the IG than in the UCG (r = -0.1). Over the course of the study, patient adherence decreased in both groups. OrCaSS is a promising intervention to delay and reduce OM. These results can serve to plan a larger RCT.


[Surgery of the Nasal Septum].
Dimension, position and stability of the cartilaginous nasal septum are crucial for successful surgery of the nasal septum. The objective of septoplasty is to create sufficient space in the anterior parts of the nose, particularly in the region of the nasal valves. Therefore, the cartilaginous nasal septum should obtain a state of "balanced tension". Essential steps of septoplasty include the hemitransfixion incision, the dissection of subperichondrial/subperiosteal tunnels, the mobilization via chondrotomy/osteotomy, the resection of cartilage/bone, the replantation of extracorporeally straightened material/reconstruction of the caudal nasal septum, closure by suture and fixation with nasal splints. Firmness of the caudal nasal septum is essential for sustainable septal surgery. It ensures the stability of the entire cartilaginous nose over decades.


Electrophysiological and optical changes in slices of rat hippocampus during spreading depression.
Spreading depression (SD) was studied with intracellular and extracellular recordings and with photometry in slices of rat hippocampus. Repetitive electrical stimulation could initiate SD in either normal medium or in low-Ca2+ medium containing Mn2+, especially during transient hypoxia. The extracellular voltage near CA1 pyramidal somata and dendrites became negative by approximately 18 mV during SD. This negativity peaked more slowly in low-Ca2+ medium containing Mn2+. The wave of negativity propagated across the slice in both media at approximately 6 mm/min. Input resistance of pyramidal neurons became undetectable during SD, and differential voltage recording between neurons and adjacent extracellular space demonstrated that transmembrane potential approached zero. Slices became more opaque during SD. Photometry revealed approximately 10% increase in reflectance and a similar decrease in transmittance of white light, which occurred with a time course similar to the extracellularly recorded voltage shift. These data support the hypothesis that SD represents a large increase in membrane permeability associated with substantial movements of water. The persistance of SD in a bathing solution that blocked electrically evoked postsynaptic potentials suggests that the contribution of synaptic transmitter release to the propagation of SD should be reappraised.


Treatment of primary brain tumours in adults.
This article considers the complexities of caring for patients with primary brain tumours. The incidence, classification and clinical signs and symptoms are outlined. Adult patients experience disabling effects as a result of a brain tumour, which is often accompanied by high morbidity and mortality rates. The various treatment options available are summarised. However, for many patients, there are limited curative treatment options and the main focus is palliative care. The nurse's contribution to care and support of these patients and their families is discussed, with the aim of improving their quality of life.


Lactobacillus crustorum sp. nov., isolated from two traditional Belgian wheat sourdoughs.
A polyphasic taxonomic study of the lactic acid bacteria (LAB) population in three traditional Belgian sourdoughs, sampled between 2002 and 2004, revealed a group of isolates that could not be assigned to any recognized LAB species. Initially, sourdough isolates were screened by means of (GTG)(5)-PCR fingerprinting. Four isolates displaying unique (GTG)(5)-PCR patterns were further investigated by means of phenylalanyl-tRNA synthase (pheS) gene sequence analysis and represented a bifurcated branch that could not be allocated to any LAB species present in the in-house pheS database. Their phylogenetic affiliation was determined using 16S rRNA gene sequence analysis and showed that the four sourdough isolates belong to the Lactobacillus plantarum group with Lactobacillus mindensis, Lactobacillus farciminis and Lactobacillus nantensis as closest relatives. Further genotypic and phenotypic studies, including whole-cell protein analysis (SDS-PAGE), amplified fragment length polymorphism (AFLP) fingerprinting, DNA-DNA hybridization, DNA G+C content analysis, growth characteristics and biochemical features, demonstrated that the new sourdough isolates represent a novel Lactobacillus species for which the name Lactobacillus crustorum sp. nov. is proposed. The type strain of the new species is LMG 23699(T) (=CCUG 53174(T)).


Workforce planning: How we think about the impact of organisations on outcomes.
Healthcare workforce availability and planning is of fundamental importance to patients, clinicians, operational managers and strategic leaders alike. Despite much attention and development of plans and policy, a definitive answer remains elusive. The aim of this article is to encourage colleagues to make explicit their underlying assumed models when undertaking workforce planning. It is posited that, akin to making a holistic diagnosis in medicine, understanding workforce issues by uncovering the prisms of presupposition and assumption that we hold about organisations is critical to generating fruitful new insights. Morgan's organisational metaphors are described as one example of a management conceptual model that might help us to illuminate these prisms. Examples are given of how each metaphor alters the way in which we might address our workforce needs and priorities.


OKCAM: an ontology-based, human-centered knowledgebase for cell adhesion molecules.
'Cell adhesion molecules' (CAMs) are essential elements of cell/cell communication that are important for proper development and plasticity of a variety of organs and tissues. In the brain, appropriate assembly and tuning of neuronal connections is likely to require appropriate function of many cell adhesion processes. Genetic studies have linked and/or associated CAM variants with psychiatric, neurologic, neoplastic, immunologic and developmental phenotypes. However, despite increasing recognition of their functional and pathological significance, no systematic study has enumerated CAMs or documented their global features. We now report compilation of 496 human CAM genes in six gene families based on manual curation of protein domain structures, Gene Ontology annotations, and 1487 NCBI Entrez annotations. We map these genes onto a cell adhesion molecule ontology that contains 850 terms, up to seven levels of depth and provides a hierarchical description of these molecules and their functions. We develop OKCAM, a CAM knowledgebase that provides ready access to these data and ontologic system at http://okcam.cbi.pku.edu.cn. We identify global CAM properties that include: (i) functional enrichment, (ii) over-represented regulation modes and expression patterns and (iii) relationships to human Mendelian and complex diseases, and discuss the strengths and limitations of these data.


Copper-catalyzed aerobic carboxygenation and N-arylation of [1,2,3]triazolo[1,5-a]pyridines towards pyridinium triazolinone ylides.
Copper-catalyzed aerobic oxyarylation of [1,2,3]triazolo[1,5-a]pyridines is developed. Notably molecular oxygen was utilized as one of the reagents and the transformation resulted in the formation of novel pyridinium triazolinone ylides. A basic mechanism for the one-pot process is proposed and further functionalization of the ylidic products were also presented.


[Silent circulation of poliovirus demonstrated by interference against non-polio enterovirus].
Fecal samples were weekly obtained from children under 3 years of age to isolate non-polio poliovirus and enterovirus and to expand the knowledge on circulation of vaccine-derived viruses during mass campaigns. The steady vaccination schedules allow the circulation of these viruses for long periods of time. The interference of non-polio enterovirus by vaccine poliovirus was demonstrated in children. However, the low percentages of non-polio enterovirus did not show significant differences whereas these differences were significant in high percentages of vaccine poliovirus isolated in children under one year-old in comparison with those of 1 and 2 years of age. Based on this contradiction, mathematical calculations estimated the silent circulation of poliovirus that in turn made it possible to draw simulated curves. The results were later confirmed in another research work by using immunological methods.


TLR4 Polymorphisms (896A>G and 1196C>T) Affect the Predisposition to Diabetic Nephropathy in Type 2 Diabetes Mellitus.
Type 2 diabetes mellitus (T2DM) is a disease with a steadily increasing incidence throughout the world. Some molecules regulating the innate immune responses such as toll-like receptor 4 (TLR4) have shown to be involved in late diabetic complications. This study aimed to investigate the association of TLR4 gene polymorphisms with clinicopathological aspects of T2DM in the Iranian population. Two TLR4 896A>G and 1196C>T polymorphisms were assessed in 100 T2DM patients and 100 healthy controls using sequence-specific primers PCR. Demographic, anthropometric, and biochemical parameters were obtained from the participants. After logistic regression, in 1196C>T, a significant association was shown between diabetic nephropathy (DN) and CT genotype (P= 0.04, OR= 4.35, CI= (1.04-18.1)). TG level has increased significantly in both T2DM and control subjects with CT genotype (P= 0.027, OR= 1.005, 95% CI= (1.001-1.01)). For 896A>G variant, a significant association was also detected between AG genotype and increased oral glucose tolerance test (OGTT) level (P= 0.048, OR= 1.003, 95% CI= (1.00-1.005)). Although minor alleles of 1196C>T and 896A>G variants have not directly been associated with type 2 diabetes, by involving in the dysregulation of serum TG and blood sugar levels, they might increase the risk of DN.


Bilateral Wallerian Degeneration of the Pontocerebellar Tracts.
Wallerian degeneration is the process of progressive demyelination and disintegration of the distal axonal segment following the transection of the axon or damage to the neuron. We report a case of a patient with Wallerian degeneration of the pontocerebellar tracts. She had a history of a pontine infarction 3 months ago. Wallerian degeneration of pontocerebellar tracts is seen bilaterally and symmetrically and is more visible in the middle cerebellar peduncles. Along the middle cerebellar peduncles hyperintense signal was detected on T2 weighted images. Wallerian degeneration of pontocerebellar tracts is a rare entity. It can occur bilaterally after a large pontine infarction. Magnetic resonance imaging seems to be the most effective technique for detection of Wallerian degeneration. In this report we want to mention this rare entity and to prevent wrong diagnosis.


Thoracic pedicle screw fixation for spinal deformity.
Techniques to improve segmental fixation have advanced the ability to correct complex spinal deformity. The purpose of instrumentation is to correct spinal deformity or to stabilize the spine to enhance the long-term biological fusion. The ultimate goal of spinal deformity surgery is the creation of a stable, balanced, pain-free spine centered over the pelvis in the coronal and sagittal planes. The minimum number of segments should be fused. These concepts remain challenging in the setting of deformity and instability. Successful results can be obtained if the surgeon understands the technology available, its capabilities, biological limitations, and the desired solution. The authors prefer to use thoracic pedicle screws when treating patients with spinal deformity because they provide greater corrective forces for realignment. This allows shorter-segment constructs and the possibility of true derotation in correction. In this article the authors focus on the use of thoracic transpedicular screw fixation in the management of complex spinal disorders and deformity.


p75NTR and DR6 Regulate Distinct Phases of Axon Degeneration Demarcated by Spheroid Rupture.
The regressive events associated with trophic deprivation are critical for sculpting a functional nervous system. After nerve growth factor withdrawal, sympathetic axons derived from male and female neonatal mice maintain their structural integrity for ∼18 h (latent phase) followed by a rapid and near unison disassembly of axons over the next 3 h (catastrophic phase). Here we examine the molecular basis by which axons transition from latent to catastrophic phases of degeneration following trophic withdrawal. Before catastrophic degeneration, we observed an increase in intra-axonal calcium. This calcium flux is accompanied by p75 neurotrophic factor receptor-Rho-actin-dependent expansion of calcium-rich axonal spheroids that eventually rupture, releasing their contents to the extracellular space. Conditioned media derived from degenerating axons are capable of hastening transition into the catastrophic phase of degeneration. We also found that death receptor 6, but not p75 neurotrophic factor receptor, is required for transition into the catastrophic phase in response to conditioned media but not for the intra-axonal calcium flux, spheroid formation, or rupture that occur toward the end of latency. Our results support the existence of an interaxonal degenerative signal that promotes catastrophic degeneration among trophically deprived axons.SIGNIFICANCE STATEMENT Developmental pruning shares several morphological similarities to both disease- and injury-induced degeneration, including spheroid formation. The function and underlying mechanisms governing axonal spheroid formation, however, remain unclear. In this study, we report that axons coordinate each other's degeneration during development via axonal spheroid rupture. Before irreversible breakdown of the axon in response to trophic withdrawal, p75 neurotrophic factor receptor-RhoA signaling governs the formation and growth of spheroids. These spheroids then rupture, allowing exchange of contents ≤10 kDa between the intracellular and extracellular space to drive death receptor 6 and calpain-dependent catastrophic degeneration. This finding informs not only our understanding of regressive events during development but may also provide a rationale for designing new treatments toward myriad neurodegenerative disorders.


Clinical analysis of anti-Ma2-associated encephalitis.
Increasing experience indicates that anti-Ma2-associated encephalitis differs from classical paraneoplastic limbic or brainstem encephalitis, and therefore may be unrecognized. To facilitate its diagnosis we report a comprehensive clinical analysis of 38 patients with anti-Ma2 encephalitis. Thirty-four (89%) patients presented with isolated or combined limbic, diencephalic or brainstem dysfunction, and four with other syndromes. Considering the clinical and MRI follow-up, 95% of the patients developed limbic, diencephalic or brainstem encephalopathy. Only 26% had classical limbic encephalitis. Excessive daytime sleepiness affected 32% of the patients, sometimes with narcolepsy-cataplexy and low CSF hypocretin. Additional hormonal or MRI abnormalities indicated diencephalic-hypothalamic involvement in 34% of the patients. Eye movement abnormalities were prominent in 92% of the patients with brainstem dysfunction, but those with additional limbic or diencephalic deficits were most affected; 60% of these patients had vertical gaze paresis that sometimes evolved to total external ophthalmoplegia. Three patients developed atypical parkinsonism, and two a severe hypokinetic syndrome with a tendency to eye closure and dramatic reduction of verbal output. Neurological symptoms preceded the tumour diagnosis in 62% of the patients. Brain MRI abnormalities were present in 74% of all patients and 89% of those with limbic or diencephalic dysfunction. Among the 34 patients with cancer, 53% had testicular germ-cell tumours. Two patients without evidence of cancer had testicular microcalcification and one cryptorchidism, risk factors for testicular germ-cell tumours. After neurological syndrome development, 17 of 33 patients received oncological treatment (nine also immunotherapy), 10 immunotherapy alone, and six no treatment. Overall, 33% of the patients had neurological improvement, three with complete recovery; 21% had long-term stabilization, and 46% deteriorated. Features significantly associated with improvement or stabilization included, male gender, age <45 years, testicular tumour with complete response to treatment, absence of anti-Ma1 antibodies and limited CNS involvement. Immunosuppression was not found to be associated with improvement but was clearly effective in some patients. Fifteen patients (10 women, five men) had additional antibodies to Ma1. These patients were more likely to have tumours other than testicular cancer and to develop ataxia, and had a worse prognosis than patients with only anti-Ma2 antibodies (two women, 21 men); 67% of deceased patients had anti-Ma1 antibodies. Anti-Ma2 encephalitis (with or without anti-Ma1 antibodies) should be suspected in patients with limbic, diencephalic or brainstem dysfunction, MRI abnormalities in these regions, and inflammatory changes in the CSF. In young male patients, the primary tumour is usually in the testis, in other patients the leading neoplasm is lung cancer.


Health care practitioners' confidence assessing lupus-related rashes in patients of color.
Background: Patients with skin of color (P-SOC) are disproportionately burdened by lupus and often have worse disease outcomes than white patients. This is partly because educational materials underrepresent P-SOC, thereby promoting unconscious bias and clinical deficiencies among practitioners.Purpose: We sought to measure providers' confidence in diagnosing the cutaneous manifestations of lupus (i.e., lupus-related rashes) in P-SOC and to assess which factors influenced their confidence.Research Design: We created and distributed a survey that gathered information about participants' personal characteristics, clinical specialty, training, and current practice as well as measuring their confidence assessing lupus-related rashes in various skin tones.Study Sample: Practitioners from the fields of rheumatology, dermatology, and internal medicine in the greater St. Louis area (Missouri, USA) participated in the survey.Analysis: We compared practitioners' mean confidence levels assessing lupus-related rashes in patients with fair skin and P-SOC with a linear mixed effects model and used univariate and multivariate linear regression models to determine if the aforementioned factors correlated with confidence.Results: Participants' mean confidence in diagnosing lupus-related rashes in P-SOC was significantly lower than assessing such findings in patients with fair skin (p = .009). Several factors correlated with confidence level at a univariate level; however, the multivariate model revealed experience as the only factor significantly associated with confidence (p = .001). Conclusions: Providers report significantly less confidence assessing lupus-related rashes in P-SOC than in patients with fair skin. Our analysis demonstrates that experience positively correlates with confidence and suggests that interventions which enhance practitioners' exposure to and experience with these rashes in P-SOC can improve clinical confidence as well as patient outcomes.


Sclerosing peritonitis associated with bilateral luteinized thecoma, linked to anticonvulsant therapy.
To present a new case of sclerosing peritonitis associated with bilateral luteinized thecoma of the ovaries, linked to anticonvulsant therapy. A 22-year-old patient, receiving carbamazepine for seizures and anxiety attacks presented with shortness of breath, abdominal pain, nausea and vomiting. Clinical and imaging examinations revealed bilateral ovarian masses with massive ascites. At emergency surgery, bilateral ovarian luteinized thecoma with sclerosing peritonitis was found. Due to recurrent, postoperative episodes of small bowel obstruction she was treated with nasogastric suction, intravenous fluids and electrolyte replacement. Total parenteral nutrition was introduced. Since only partial improvement was achieved tamoxifen was administered with resolution of the bowel obstruction. This is the 19th case of sclerosing peritonitis associated with luteinized thecoma of the ovaries and the 3rd to be associated with anticonvulsant therapy. Treatment should be aimed at relief of bowel obstruction symptoms, preferably with conservative methods. Tamoxifen for downregulation of TGF-beta production should be considered as a treatment modality, as it proved to be very helpful in the presented patient.


Inactivation of acetylcholine release from Torpedo synaptosomes in response to prolonged depolarizations.
The release of acetylcholine (ACh) from purely cholinergic Torpedo synaptosomes was monitored continuously using a chemiluminescent assay (Israël & Lesbats, 1981 a, b). Upon prolonged K+ depolarization in the presence of Ca2+, the release of ACh was transient and returned to a steady low level in about 3 min. Addition of the Ca2+ ionophore A23187 triggered the release again, suggesting that neither depletion of the transmitter store nor an inhibition of the release mechanism itself were involved in this phasic response, but rather an inactivation of the Ca2+ entry. The release response evoked by adding Ca2+ back after exposure of the synaptosomes to high K+ (70 mM) and low Ca2+ (0.57 mM) solution inactivates as a function of the duration of the pre-depolarization with a two-component time course with rapid (tau = 5.5 s) and slow phases (tau = 143 s). This response to Ca2+ addition was more strikingly reduced as the level of depolarization during pre-treatment was increased. The inactivation was found to be dose dependent with respect to the amount of Ca2+ present during the pre-depolarization period (conditioning Ca2+). Moreover, the presence of EGTA during pre-treatment with high-K+ solutions increased the response to applied Ca2+. These observations suggest that Ca2+ entry itself was responsible for this inactivation. No inactivation was found when ACh release was induced by the depolarizing agent Gramicidin D, except when external Na+ was replaced by Li+. This result indicates that part of the Ca2+ influx promoted by Gramicidin D depends on a Na+ entry, and may be mediated by the Na-Ca exchange mechanism.


Influence of antioxidant rich fresh vegetable juices on starch induced postprandial hyperglycemia in rats.
This research analyzed the major chemical components and multiple antioxidant activities present in the fresh juice of eight vegetables, and studied their influence on starch induced postprandial glycemia in rats. A SDS-PAGE based protein fingerprint of each vegetable juice was also prepared. The yields of juice, chemical components like total proteins, total polyphenols, total flavonoids, total anthocyanins and free radicals like the ABTS˙(+) cation, DPPH, H(2)O(2), scavenging activities and reducing properties for NBT and FeCl(3) showed wide variations. Vegetable juice from brinjal ranked first in displaying total antioxidant capacity. Pretreatment of rats with vegetable juices moderated starch induced postprandial glycemia. The fresh juice from the vegetables ridge gourd, bottle gourd, ash gourd and chayote significantly mitigated postprandial hyperglycemic excursion. Total polyphenol concentrations present in vegetable juices positively influenced ABTS˙(+) scavenging activity and total antioxidant capacity. However, NBT reducing activity of juices was positively affected by total protein concentration. Contrarily, however, high polyphenol content in vegetable juice was observed to adversely affect the postprandial antihyperglycemic activity of vegetable juices. This is the first report exploring antihyperglycemic activity in these vegetable juices and highlights the possible adverse influence of high polyphenol content on the antihyperglycemic activity of the vegetable juices.


High incidence of HPV-associated head and neck cancers in FA deficient mice is associated with E7's induction of DNA damage through its inactivation of pocket proteins.
Fanconi anemia (FA) patients are highly susceptible to solid tumors at multiple anatomical sites including head and neck region. A subset of head and neck cancers (HNCs) is associated with 'high-risk' HPVs, particularly HPV16. However, the correlation between HPV oncogenes and cancers in FA patients is still unclear. We previously learned that FA deficiency in mice predisposes HPV16 E7 transgenic mice to HNCs. To address HPV16 E6's oncogenic potential under FA deficiency in HNCs, we utilized HPV16 E6-transgenic mice (K14E6) and HPV16 E6/E7-bi-transgenic mice (K14E6E7) on genetic backgrounds sufficient or deficient for one of the fanc genes, fancD2 and monitored their susceptibility to HNCs. K14E6 mice failed to develop tumor. However, E6 and fancD2-deficiency accelerated E7-driven tumor development in K14E6E7 mice. The increased tumor incidence was more correlated with E7-driven DNA damage than proliferation. We also found that deficiency of pocket proteins, pRb, p107, and p130 that are well-established targets of E7, could recapitulate E7's induction of DNA damage. Our findings support the hypothesis that E7 induces HPV-associated HNCs by promoting DNA damage through the inactivation of pocket proteins, which explains why a deficiency in DNA damage repair would increase susceptibility to E7-driven cancer. Our results further demonstrate the unexpected finding that FA deficiency does not predispose E6 transgenic mice to HNCs, indicating a specificity in the synergy between FA deficiency and HPV oncogenes in causing HNCs.


The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells.
Translocations involving fibroblast growth factor receptor 3 (fgfr3) have been identified in about 25% of patients with myeloma. To directly examine the oncogenic potential of fgfr3, murine bone marrow (BM) cells were transduced with retroviral vectors containing either wild-type fgfr3 or an activated mutant form of the receptor, fgfr3-TD. Mice transplanted with FGFR3-TD-expressing BM developed a marked leukocytosis and lethal hematopoietic cell infiltration of multiple tissues within 6 weeks of transplantation. Secondary and tertiary recipients of spleen or BM from primary fgfr3-TD mice also developed tumors within 6 to 8 weeks. Analysis of the circulating tumor cells revealed a pre-B-cell phenotype in most mice, although immature T-lymphoid or mature myeloid populations also predominated in some animals. Enhanced lymphoid but not myeloid colony formation was observed in the early posttransplantation period and only interleukin 7 and FGF-responsive pre-B-cell lines could be established from tumors. Cell expansions in primary recipients appeared polyclonal, whereas tumors in later passages exhibited either clonal B- or T-cell receptor gene rearrangements. Mice transplanted with wild-type FGFR3-expressing BM developed delayed pro-B-cell lymphoma/leukemias approximately 1 year after transplantation. These studies confirm that FGFR3 is transforming and can produce lymphoid malignancies in mice.


Heparanase-A Link between Coagulation, Angiogenesis, and Cancer.
Heparanase that was cloned from and is abundant in the placenta is implicated in cell invasion, tumor metastasis, and angiogenesis. Recently we have demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. Heparanase was shown to up-regulate tissue factor (TF) expression and interact with tissue factor pathway inhibitor (TFPI) on the cell surface, leading to dissociation of TFPI from the cell membrane of endothelial and tumor cells, resulting in increased cell surface coagulation activity. More recently, we have shown that heparanase directly enhances TF activity, resulting in increased factor Xa production and activation of the coagulation system. Data indicate increased levels and possible involvement of heparanase in vascular complications in pregnancy. Taking into account the prometastatic and proangiogenic functions of heparanase, overexpression in human malignancies, and abundance in platelets and placenta, its involvement in the coagulation machinery is an intriguing novel arena for further research.


Effect of network size on comparing different stock networks.
We analyzed complex networks generated by the threshold method in the Korean and Indian stock markets during the non-crisis period of 2004 and the crisis period of 2008, while varying the size of the system. To create the stock network, we randomly selected N stock indices from the market and constructed the network based on cross-correlation among the time series of stock prices. We computed the average shortest path length L and average clustering coefficient C for several ensembles of generated stock networks and found that both metrics are influenced by network size. Since L and C are affected by network size N, a direct comparison of graph measures between stock networks with different numbers of nodes could lead to erroneous conclusions. However, we observed that the dependency of network measures on N is significantly reduced when comparing larger networks with normalized shortest path lengths. Additionally, we discovered that the effect of network size on network measures during the crisis period is almost negligible compared to the non-crisis periods.


No more winter crisis? Forecasting daily bed requirements for emergency department admissions to hospital.
We hypothesized that age, calendar variables, and clinical influenza epidemics may have an impact on the number of daily through-emergency department (ED) hospitalizations. The aim of our study was to elaborate a pragmatic tool to predict the daily number of through-ED hospitalizations. We carried out a prospective-observational study including data from 18 ED located in the Paris metropolitan area. Daily through-ED hospitalizations numbers from 2007 to 2010 were modelized to forecast the year 2011 using a general linear model by age groups (<75-years; ≥75-years) using calendar variables and influenza epidemics as explanatory variables. Lower and higher limits forecast with the 95% confidence interval of each explanatory variable were calculated. 2 741 974 ED visits and 518 857 through-ED hospitalizations were included. We found a negative trend (-2.7%) for hospitalization visits among patients less than 75 years of age and an increased trend (+6.2%) for patients of at least 75 years of age. Calendar variables were predictors for daily hospitalizations for both age groups. Influenza epidemic period was not a predictor for hospitalizations in patients less than 75 years of age; among patients of at least 75 years of age, significant value was found only in models excluding months. When forecasting hospitalizations, 70% for patients less than 75 years of age and 66.8% for patients of at least 75 years of age of daily predicted values were included in the forecast limits. Daily number of emergency hospitalizations could be predicted on a regional basis using calendar variables with a low level of error. Forecasting through-ED hospitalizations requires to differentiate between elderly and younger patients, with a low impact of influenza epidemic periods in elders and absent in youngest patients.


Automatic assignment of absolute configuration from 1D NMR data.
[reaction: see text] Opposite enantiomers exhibit different NMR properties in the presence of an external common chiral element, and a chiral molecule exhibits different NMR properties in the presence of external enantiomeric chiral elements. Automatic prediction of such differences, and comparison with experimental values, leads to the assignment of the absolute configuration. Here two cases are reported, one using a dataset of 80 chiral secondary alcohols esterified with (R)-MTPA and the corresponding (1)H NMR chemical shifts and the other with 94 (13)C NMR chemical shifts of chiral secondary alcohols in two enantiomeric chiral solvents. For the first application, counterpropagation neural networks were trained to predict the sign of the difference between chemical shifts of opposite stereoisomers. The neural networks were trained to process the chirality code of the alcohol as the input, and to give the NMR property as the output. In the second application, similar neural networks were employed, but the property to predict was the difference of chemical shifts in the two enantiomeric solvents. For independent test sets of 20 objects, 100% correct predictions were obtained in both applications concerning the sign of the chemical shifts differences. Additionally, with the second dataset, the difference of chemical shifts in the two enantiomeric solvents was quantitatively predicted, yielding r(2) 0.936 for the test set between the predicted and experimental values.


Craniofacial development in the talpid3 chicken mutant.
The talpid(3) chicken mutant has a pleiotropic phenotype including polydactyly and craniofacial abnormalities. Limb polydactyly in talpid(3) suggests a gain of Hedgehog (Hh) signaling, whereas, paradoxically, absence of midline facial structures suggests a loss of Hh function. Here we analyze the status of Shh signaling in the talpid(3) mutant head. We show that Shh expression domains are lost from the talpid(3) head--in hindbrain, midbrain, zona limitans intrathalamica, and stomodeal ectoderm--and that direct targets of Hedgehog signaling, Ptc1, Ptc2, and Gli1, are also absent even in areas associated with primary Shh expression. These data suggest that the talpid(3) mutation leads to defective activation of the Shh pathway and, furthermore, that tissue-to-tissue transduction of Shh expression in the developing head depends on Hh pathway activation. Failure to activate the Shh pathway can also explain absence of floor plate and Hnf-3beta and Netrin-1 expression in midbrain and hindbrain and absence of Fgf-8 expression in commissural plate. Other aspects of gene expression in the talpid(3) head, however, suggest misspecification, such as maintenance of floor plate-like gene expression in telencephalon. In branchial arches and lower jaw, where Shh is expressed, changes in expression of genes involved in patterning and mesodermal specification suggest both gain and loss of Hedgehog function. Thus, analysis of gene expression in talpid(3) head shows that, as in talpid(3) limb, expression of some genes is lost, while others are ectopically expressed. Unlike the limb, many head regions depend on Hh induction of a secondary domain of Shh expression, and failure of this induction in talpid(3), together with the inability to activate the Shh pathway, explain the loss-of-function head phenotype. This gene expression analysis in the talpid(3) head also confirms and extends knowledge of the importance of Shh signaling and the balance between activation and repression of Shh targets in many aspects of craniofacial morphogenesis.


Determinant for beta-subunit regulation in high-conductance voltage-activated and Ca(2+)-sensitive K+ channels: an additional transmembrane region at the N terminus.
The pore-forming alpha subunit of large conductance voltage- and Ca(2+)-sensitive K (MaxiK) channels is regulated by a beta subunit that has two membrane-spanning regions separated by an extracellular loop. To investigate the structural determinants in the pore-forming alpha subunit necessary for beta-subunit modulation, we made chimeric constructs between a human MaxiK channel and the Drosophila homologue, which we show is insensitive to beta-subunit modulation, and analyzed the topology of the alpha subunit. A comparison of multiple sequence alignments with hydrophobicity plots revealed that MaxiK channel alpha subunits have a unique hydrophobic segment (S0) at the N terminus. This segment is in addition to the six putative transmembrane segments (S1-S6) usually found in voltage-dependent ion channels. The transmembrane nature of this unique S0 region was demonstrated by in vitro translation experiments. Moreover, normal functional expression of signal sequence fusions and in vitro N-linked glycosylation experiments indicate that S0 leads to an exoplasmic N terminus. Therefore, we propose a new model where MaxiK channels have a seventh transmembrane segment at the N terminus (S0). Chimeric exchange of 41 N-terminal amino acids, including S0, from the human MaxiK channel to the Drosophila homologue transfers beta-subunit regulation to the otherwise unresponsive Drosophila channel. Both the unique S0 region and the exoplasmic N terminus are necessary for this gain of function.


A Network-Based Cancer Drug Discovery: From Integrated Multi-Omics Approaches to Precision Medicine.
A complex framework of interacting partners including genetic, proteomic, and metabolic networks that cooperate to mediate specific functional phenotypes drives human biological processes. Recent technological and analytical advances in "omic" sciences allow the identification and elucidation of reprogramming biological functions in response to perturbations in cells and tissues. To understand such a complex system, biological networks are generated to reduce the complexity into relatively simple models, and the integration of these molecular networks from different perspectives is implemented for a holistic interpretation of the entire system. Ultimately, network-based methods will effectively facilitate the development and improvement of precision medicine by directing therapies based on the underlying biology of a given patient's disease. The goal of precision medicine is to identify novel therapeutic strategies that can be optimized for each disease type or each patient based on the underlying genetic, environmental, and lifestyle factors. Pharmaco-omics analyses based on an integration of pharmacology and various "omics" data types can be employed to develop effective treatment strategies using particular drugs and doses that are tailored to each individual. In the current review, we first present the core elements of network-based systems biology in the context of pharmaco-omics followed by integration of multi-omics data using various biological networks. Next, we provide an opening into precise medicine and drug targeting based on network approaches. Lastly, we review the current significant efforts as well as the accomplishments and limitations in precise drug targeting with the utility of network-based guided drug discovery methods for effective treatment of breast cancer.


Microbial aetiology of acute diarrhoea in children under five years of age in Khartoum, Sudan.
Diarrhoea is one of leading causes of morbidity and mortality worldwide. Recent estimations suggested the number of deaths is close to 2.5 million. This study examined the causative agents of diarrhoea in children under 5 years of age in suburban areas of Khartoum, Sudan. A total of 437 stool samples obtained from children with diarrhoea were examined by culture and PCR for bacteria, by microscopy and PCR for parasites and by immunoassay for detection of rotavirus A. Of the 437 samples analysed, 211 (48%) tested positive for diarrhoeagenic Escherichia coli, 96 (22%) for rotavirus A, 36 (8%) for Shigella spp., 17 (4%) for Salmonella spp., 8 (2%) for Campylobacter spp., 47 (11%) for Giardia intestinalis and 22 (5%) for Entamoeba histolytica. All isolates of E. coli (211, 100 %) and Salmonella (17, 100%), and 30 (83%) isolates of Shigella were sensitive to chloramphenicol; 17 (100%) isolates of Salmonella, 200 (94%) isolates of E. coli and (78%) 28 isolates of Shigella spp. were sensitive to gentamicin. In contrast, resistance to ampicillin was demonstrated in 100 (47%) isolates of E. coli and 16 (44%) isolates of Shigella spp. In conclusion, E. coli proved to be the main cause of diarrhoea in young children in this study, followed by rotavirus A and protozoa. Determination of diarrhoea aetiology and antibiotic susceptibility patterns of diarrhoeal pathogens and improved hygiene are important for clinical management and controlled strategic planning to reduce the burden of infection.


The Stability of Augmented Bone Between Two Different Membranes Used for Guided Bone Regeneration Simultaneous with Dental Implant Placement in the Esthetic Zone.
This randomized controlled clinical trial compared the stability of augmented bone between a synthetic resorbable membrane and a collagen resorbable membrane with guided bone regeneration (GBR) simultaneous with dental implant placement in the esthetic zone in terms of facial bone thickness. A total of 60 dental implants from patients requiring implant placement with simultaneous GBR in the esthetic zone were equally allocated to the test group or control group by block randomization. Biphasic calcium phosphate ceramic bone was used in combination with either a polylactic acid (PLA) membrane (test group, 30 implants) or a resorbable collagen membrane (control group, 30 implants). Cone beam computed tomographic (CBCT) images were used to assess the facial bone thickness postimplantation and then 6 months later at four levels: implant platform and 2 mm, 4 mm, and 6 mm apical to the implant shoulder. All implants were osseointegrated, and no implant loss was found during this study. Facial bone was detected in all cases; however, the thickness of the facial bone was reduced at the 6-month follow-up in both groups. The percentage of facial bone thickness reduction was 34.30%, 27.94%, 24.25%, and 19.81% in the test group and 34.80%, 24.06%, 19.52%, and 20.45% in the control group at the level of the implant platform and at 2 mm, 4 mm, and 6 mm apical to the implant shoulder, respectively. Nevertheless, there was no statistically significant difference between the groups (P > .05). A synthetic resorbable membrane revealed an amount of stable augmented bone similar to that of a collagen resorbable membrane.


Fourier-based analysis of moiré fringe patterns of superposed gratings in alignment of nanolithography.
Considering the necessity of alignment in practical applications of photolithography, distribution of complex amplitude of moiré fringe patterns that are produced in superposition of two gratings is analyzed in the viewpoint of Fourier Optics and the relationship between fringes and properties of these two gratings is concluded by means of an analysis model. The rule of one-dimensional gratings (1D-gratings) is extended to other form of the gratings which have quasi-periodic repetitive structures. Especially, moiré fringes generated by the two superposed 1D-gratings (used in alignment of lithography) can be expressed by an arithmetical operation of two vectors which include enough information about these 1D-gratings. Numerical analyses regarding the moiré model and its application in the alignment process of lithography are carried out. Our computational analyses results show that the moiré fringes of the two extended gratings can be refined as a transformed fringe pattern of two standard 1D-gratings. Finally, the results also make it out that the fringes which have magnified periods versus that of two 1D-gratings are highly sensitive to relative shift of two gratings thus might be applicable in alignment of lithography or correlated fields.


The major outer-membrane proteins of Chlamydia trachomatis serovars A and B: intra-serovar amino acid changes do not alter specificities of serovar- and C subspecies-reactive antibody-binding domains.
The major outer-membrane protein (MOMP) of Chlamydia trachomatis is a promising candidate antigen for chlamydial vaccine development. We have sequenced the MOMP genes for a serovar A and a serovar B isolate and have compared these new sequences with those already reported. Intra-serovar changes in the inferred amino acid sequences of the surface-exposed variable segments known to be responsible for binding of neutralizing antibody were observed. Nevertheless, epitope mapping with solid-phase peptides showed that these intra-serovar changes did not affect the binding of serovar- and subspecies-specific, potentially protective antibodies. Variable segment 1 of C. trachomatis serovar A contained two adjacent antibody-binding sites, one of which was C-subspecies specific while the other was serovar A specific. Therefore the subspecies binding site for C-complex organisms is in variable segment 1, whilst that for B-complex organisms is in variable segment 4. This work shows that MOMP sequences are relatively stable within the serovar categorization for isolates taken decades apart from different continents. Within a given serovar, however, limited interchange of functionally related amino acids may occur without impairing the binding of serovar-specific antibody.


Field Evaluation of the Ultrasonic Personal Aerosol Sampler (UPAS) for Respirable Dust Exposure in a Taconite Mine.
Exposure to respirable dust (RD; the mass fraction of inhaled particles that penetrate to the unciliated airways) is a major health concern in a variety of workplaces. While the estimation of personal exposure is an essential step in protecting worker health from aerosol hazards, the traditional method for assessing personal exposure to RD, suggested by the National Institute for Occupational Safety and Health (NIOSH method 0600), requires equipment that is heavy, bulky, noisy, and has the need of frequent calibration. The ultrasonic personal aerosol sampler (UPAS) is a new personal sampling technology designed to address some of these drawbacks associated with traditional sampling methods. In this study, we field tested and evaluated the performance of the UPAS for assessing worker exposure to RD in a taconite mine. Mineworkers (n = 39) from various job categories were recruited to wear both UPAS and NIOSH 0600 samplers on a work vest to estimate time-weighted exposure to RD. A strong linear relationship was observed (NIOSH method 0600 = 1.06 (UPAS) -9.22 µg m-3, r2 of 0.72, and Pearson correlation coefficient of 0.854). None of the workers were exposed to a RD concentration above the Occupational Safety and Health Administration permissible exposure limit (5 mg m-3). A Bland-Altman analysis revealed that 72% of the valid UPAS samples agreed within ±25% of the traditional method mean. The impact of job category on the correlation of the methods was not statistically significant. This work suggests that the UPAS may present a viable alternative for assessing personal exposure to RD in the workplace.


A chemically modified tetracycline inhibits streptozotocin-induced diabetic depression of skin collagen synthesis and steady-state type I procollagen mRNA.
Wasting of connective tissues including skin, bone, and cartilage have been closely associated with elevated matrix metalloproteinase (MMP) activity and depressed collagen content in the streptozotocin (STZ)-induced diabetic rat, while tetracyclines have been reported to normalize total body weight, skin hydroxyproline and collagen content in this model, in part through inhibition of MMPs. In the present study, we report the effect of CMT-1, a chemically modified tetracycline that lacks antimicrobial properties but retains divalent cation binding and MMP inhibitory activity, on diabetic skin collagen synthesis and steady-state levels of procollagen alpha 1(I) mRNA. Male, 4-month old Sprague-Dawley rats received a single injection of 75 mg/kg STZ or citrate vehicle alone and diabetic status was confirmed by positive glucosuria. Some diabetic animals received 10 mg/day of CMT-1 by oral gavage and, 28 days after STZ treatment, body weight, blood glucose values and the in vivo rates of skin collagen production were measured using the pool-expansion technique. Steady-state levels of procollagen alpha 1(I) mRNA were analyzed 21 days after STZ treatment by hybridization of total RNA with a 32P labelled cDNA to rat type I procollagen alpha 1(I) mRNA in a dot-blot assay. STZ treatment was found to significantly depress body weight, skin collagen hydroxyproline content, the in vivo rate of collagen production, and hybridizable levels of type I procollagen alpha 1(I) mRNA. CMT-1 administered daily to STZ-treated rats inhibited the diabetic depression of these parameters but had little or no effect on non-diabetic controls or on STZ-induced hyperglycemia. Thus, in addition to the inhibition of MMP mediated extracellular collagen degradation, these results suggest CMT-1 also acts to inhibit diabetic connective tissue breakdown in STZ-induced diabetes by increasing both steady-state levels of type I procollagen mRNA and collagen synthesis through mechanism(s) that are independent of the antibacterial properties of tetracyclines.


The control of cell division in articular chondrocytes.
Our objective was to investigate the factors that control chondrocyte division, namely, (1) steric hindrance caused by the surrounding matrix, (2) growth factors and (3) cell shape. Bovine articular cartilage explants and isolated chondrocytes were cultured in medium containing [3H]-TdR to measure DNA synthesis. The effect of enzyme treatment, growth factors and cell shape was investigated. Proteoglycan (PG) depletion did not stimulate DNA synthesis whilst disruption of the collagen architecture promoted incorporation of [3H]-TdR into DNA. DNA synthesis was also stimulated by IGF-1 in flattened chondrocytes but not in rounded cells. It was found that the control of chondrocyte division depends on several variably related factors that may act singly or together to induce cell division and that PG depletion alone is insufficient to induce DNA synthesis, but division was noted when PG depletion was accompanied by matrix disruption and cell shape changes. Cell shape appears to alter the chondrocytes ability to respond to IGF-1 as a mitogen.


The T 11 (CD 2) cDNA encodes a transmembrane protein which expresses T 11(1), T 11(2) and T 11(3) epitopes but which does not independently mediate calcium influx: analysis by gene transfer in a baculovirus system.
To determine whether a full-length human T 11 (CD 2) cDNA encodes a protein which expresses all three T 11 epitopes (T 11(1), T 11(2), T 11(3] and independently triggers activation in a cell other than a T lymphocyte, a baculovirus expression system was employed. Here we show that a recombinant T 11 cDNA-containing baculovirus can induce high-level expression of T 11(1), T 11(2) and T 11(3) epitopes on the surface of gut epithelial SF9 cells. However, in this environment the T 11 protein cannot be triggered to transduce a signal resulting in an elevation of the cytosolic free Ca2+ as is known to occur in T lymphocytes. These results support the notion that T 11 functions in a coordinate fashion with other intracellular lymphoid components.


Effects of mucopolysaccharides on penicillin-induced lysis of Staphylococcus aureus.
Effects of four mucopolysaccharides and dextran sulphate on penicillin-induced lysis of Staphylococcus aureus FDA 209P were studied. Heparin and dextran sulphate inhibited lysis, whereas hyaluronic acid enhanced it. Chondroitin sulphates A and C had no effect. Incubation of S. aureus suspended in 0.03 M phosphate buffer (pH 7.0) with dextran sulphate inhibited autolysis of the bacteria, whereas incubation with hyaluronic acid enhanced autolysis. Both extracellular and cell-associated autolysin activities of S. aureus were suppressed by dextran sulphate and high concentrations of heparin. The addition of hyaluronic acid enhanced autolysin activity. The release of lipoteichoic acid (LTA), a modulator of autolysin activity, from penicillin-treated bacteria was inhibited by heparin and dextran sulphate. However, hyaluronic acid had no effect on release of LTA. These results suggest that inhibition of penicillin-induced lysis of S. aureus by heparin results mainly from inhibition of LTA release while dextran sulphate inhibits both autolysin activity and LTA release. Hyaluronic acid appears to enhance penicillin-induced lysis through activation of the autolysins.


A classification of endangered high-THC cannabis (Cannabis sativa subsp. indica) domesticates and their wild relatives.
Two kinds of drug-type Cannabis gained layman's terms in the 1980s. "Sativa" had origins in South Asia (India), with early historical dissemination to Southeast Asia, Africa, and the Americas. "Indica" had origins in Central Asia (Afghanistan, Pakistan, Turkestan). We have assigned unambiguous taxonomic names to these varieties, after examining morphological characters in 1100 herbarium specimens, and analyzing phytochemical and genetic data from the literature in a meta-analysis. "Sativa" and "Indica" are recognized as C. sativa subsp. indica var. indica and C. sativa subsp. indica var. afghanica, respectively. Their wild-growing relatives are C. sativa subsp. indica var. himalayensis (in South Asia), and C. sativa subsp. indica var. asperrima (in Central Asia). Natural selection initiated divergence, driven by climatic conditions in South and Central Asia. Subsequent domestication drove further phytochemical divergence. South and Central Asian domesticates can be distinguished by tetrahydrocannabinol and cannabidiol content (THC/CBD ratios, ≥7 or <7, respectively), terpenoid profiles (absence or presence of sesquiterpene alcohols), and a suite of morphological characters. The two domesticates have undergone widespread introgressive hybridization in the past 50 years. This has obliterated differences between hybridized "Sativa" and "Indica" currently available. "Strains" alleged to represent "Sativa" and "Indica" are usually based on THC/CBD ratios of plants with undocumented hybrid backgrounds (with so-called "Indicas" often delimited simply on possession of more CBD than "Sativas"). The classification presented here circumscribes and names four taxa of Cannabis that represent critically endangered reservoirs of germplasm from which modern cannabinoid strains originated, and which are in urgent need of conservation.


Recombinant human hyaluronidase PH20 does not stimulate an acute inflammatory response and inhibits lipopolysaccharide-induced neutrophil recruitment in the air pouch model of inflammation.
Hyaluronidase (Hyal) and low m.w. hyaluronan (LMW HA) fragments have been widely reported to stimulate the innate immune response. However, most hyaluronidases used were purified from animal tissues (e.g., bovine testis Hyal [BTH]), and contain endotoxin and other unrelated proteins. We tested a highly purified recombinant human Hyal (rHuPH20) and endotoxin-free HA fragments from M(r) 5,000 to 1,500,000 in the rodent air pouch model of inflammation to determine their potential for stimulation of the innate immune response. Exogenous LMW HA fragments (average M(r) 200,000) failed to induce either cytokine/chemokine production or neutrophil infiltration into the air pouch. Challenging the air pouch with LPS or BTH stimulated production of cytokines and chemokines but rHuPH20 did not, suggesting that neither PH20 nor generation of LMW HA fragments in situ stimulates cytokine and chemokine production. LPS and BTH also induced neutrophil infiltration into the air pouch, which was not observed with rHuPH20 treatment. Endotoxin-depleted BTH had much reduced proinflammatory activity, suggesting that the difference in inflammatory responses between rHuPH20 and BTH is likely due to endotoxin contaminants in BTH. When rHuPH20 was dosed with LPS, the induction of cytokines and chemokines was the same as LPS alone, but neutrophil infiltration was inhibited, likely by interrupting HA-CD44 interaction. Our results indicate that neither rHuPH20 nor its directly generated HA catabolites have inflammatory properties in the air pouch model, and rHuPH20 can instead inhibit some aspects of inflammation, such as neutrophil infiltration into the air pouch.


Preclinical Risk Evaluation of Normal Tissue Injury With Novel Radiosensitizers.
Genotoxic damage induced by radiation triggers a highly coordinated DNA damage response, and molecular inhibitors of key nodes within this complex response network can profoundly enhance the antitumor efficacy of radiation. This is especially true for drugs targeting the catalytic subunit of DNA-dependent protein kinase, which is a core component of the nonhomologous end-joining DNA repair pathway, and ataxia telangiectasia mutated, which coordinates cell cycle arrest, apoptosis, and DNA repair functionalities after radiation exposure. Unlike the more modest in vitro radiosensitizing effects seen with classic sensitizing agents such as cisplatin, 5-fluorouracil, or taxanes, DNA-dependent protein kinase or ataxia telangiectasia mutated inhibitors provide much more robust sensitizing effects in vitro, as might be anticipated from targeting these key DNA repair modulators. However, patients with homozygous inactivating mutations of ataxia telangiectasia mutated or mice with homozygous defects in DNA-dependent protein kinase (severe combined immunodeficiency) have profoundly enhanced acute normal tissue radiation reactions. Therefore, there is significant potential that the combination of small molecule inhibitors of these kinases with radiation could cause similar dose-limiting acute normal tissue toxicities. Similarly, although less understood, inhibition of these DNA repair response pathways could markedly increase the risk of late radiation toxicities. Because these potent radiosensitizers could be highly useful to improve local control of otherwise radiation-resistant tumors, understanding the potential for elevated risks of radiation injury is essential for optimizing therapeutic ratio and developing safe and informative clinical trials. In this review, we will discuss 2 straightforward models to assess the potential for enhanced mucosal toxicity in the oral cavity and small intestine established in our laboratories. We also will discuss similar strategies for evaluating potential drug-radiation interactions with regard to increased risks of debilitating late effects.


Single Measurements of Carboxy-Terminal Fibroblast Growth Factor 23 and Clinical Risk Prediction of Adverse Outcomes in CKD.
An elevated fibroblast growth factor 23 (FGF-23) level is independently associated with adverse outcomes in populations with chronic kidney disease, but it is unknown whether FGF-23 testing can improve clinical risk prediction in individuals. Prospective cohort study. Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,789). Baseline carboxy-terminal FGF-23 (cFGF-23) level. All-cause and cardiovascular (CV) mortality, incident end-stage renal disease (ESRD), heart failure (HF) admission, and atherosclerotic events at 3, 5, and 8 years. We assessed changes in model performance by change in area under the receiver operating characteristic curve (ΔAUC), integrated discrimination improvement (IDI), relative IDI, and net reclassification index (NRI) above standard clinical factors. We performed sensitivity analyses, including an additional model comparing the addition of phosphate rather than cFGF-23 level and repeating our analyses using an internal cross-validation cohort. Addition of a single baseline value of cFGF-23 to a base prediction model improved prediction of all-cause mortality (ΔAUC, 0.017 [95% CI, 0.001-0.033]; IDI, 0.021 [95% CI, 0.006-0.036]; relative IDI, 32.7% [95% CI, 8.5%-56.9%]), and HF admission (ΔAUC, 0.008 [95% CI, 0.0004-0.016]; IDI, 0.019 [95% CI, 0.004-0.034]; relative IDI, 10.0% [95% CI, 1.8%-18.3%]), but not CV mortality, ESRD, or atherosclerotic events at 3 years of follow-up. The NRI did not reach statistical significance for any of the 3-year outcomes. The incremental predictive utility of cFGF-23 level diminished in analyses of the 5- and 8-year outcomes. The cFGF-23 models outperformed the phosphate model for each outcome. Power to detect increased CV mortality likely limited by low event rate. The NRI is not generalizable without accepted prespecified risk thresholds. Among individuals with CKD, single measurements of cFGF-23 improve prediction of risks for all-cause mortality and HF admission but not CV mortality, ESRD, or atherosclerotic events. Future studies should evaluate the predictive utility of repeated cFGF-23 testing.


Increased arterial stiffness in subjects with pre-diabetes among middle aged population in Beijing, China.
To investigate the relationship between arterial stiffness and pre-diabetes when assessed by the new glycosylated hemoglobin A1c (HbA1c) 5.7%-6.4% criterion or by impaired fasting glucose in middle aged Chinese. 1122 adults aged 55 years or younger in the health examination centers for physical check-ups were enrolled in the two large-sized Tertiary Comprehensive Hospitals in Beijing from June 2011 to June 2012 after excluding those who previously had been diagnosed or treated as diabetes or cardiovascular disease. Subjects with a diagnosis of pre-diabetes according to impaired fasting glucose (IFG) (fasting plasma glucose (FPG) levels at 5.6-6.9 mmol/L), HbA1c levels at 5.7%-6.4%, or both, were classified into four groups for observation: (1) Normoglycaemia (HbA1c<5.7% and FPG <5.6 mmol/L); (2) IFG alone (FPG levels at 5.6-6.9 mmol/L and HbA1c<5.7% ); (3) HbA1c 5.7%-6.4% alone (HbA1c levels at 5.7%-6.4% and FPG <5.6 mmol/L); and (4) both HbA1c 5.7%-6.4% and IFG (HbA1c levels at 5.7%-6.4% and FPG levels at 5.6-6.9 mmol/L). All subjects were measured for weight, height, waist circumference, blood pressure, fasting plasma glucose, HbA1c, lipid profile and brachial-ankle pulse wave velocity (baPWV). The mean values of baPWV were 1282±8, 1311±10, 1398±30, and 1418±27 cm/s (Mean±SE) in Normoglycaemia, HbA1c 5.7%-6.4% alone, IFG alone and the both HbA1c 5.7%-6.4% and IFG groups, respectively. After adjusting for age, gender, blood pressure, BMI and triglyceride, baPWV was significantly higher in subjects with both HbA1c 5.7%-6.4% and IFG compared among the subjects with Normoglycaemia (1350±14 vs. 1301±6 cm/s, P=0.002) and HbA1c 5.7%-6.4% alone (1350±14 vs. 1309±8 cm/s, P=0.013). Subjects with pre-diabetes exhibited a greater arterial stiffness.


The crural interosseous membrane re-visited: a histological and microscopic study.
The aim of this study was to characterize the microscopic structure and sensory nerve endings of the crural interosseous membrane (IM). 13 IMs from 7 cadavers were used to analyze the organization of the collagen fibers, IM's thickness, distribution of elastic fibers and nerve elements. The IM is mainly a two-layer collagen fascicle structure with the collagen fibers of adjacent layers orientated along different directions, forming angles of 30.5 +/- 1.7° at proximal and 26.6 +/- 2.1° at distal part (P>0.05). The percentage of elastic fibers between the two layers and inside the collagen fascicle layer is 10.1 +/- 0.5% and 2.2 +/- 0.1% (P<0.001). The IM's thickness at proximal, middle, and distal parts is 268.5 +/- 18.6μm; 293.2 +/- 12.5μm; 365.3 +/- 19.3 μm, respectively (Proximal vs Distal: P<0.001; Middle vs Distal: P<0.05). Nerve elements were present and located both inside and on the surface of the IM, whereas the mechanoreceptors are mainly located on the surface of the IM. Free nerve endings (33.3 +/- 5.0/cm2) and Ruffini corpuscles (3.4 +/- 0.6/cm2) were the predominant sensory elements, while Pacinian corpuscles (1.3 +/- 0.7/cm2) were rarely found. The type of mechanoreceptors found suggests that the IM may play a role in proprioception.


Temporal and Isoform-Specific Expression of CTBP2 Is Evolutionarily Conserved Between the Developing Chick and Human Retina.
Complex transcriptional gene regulation allows for multifaceted isoform production during retinogenesis, and novel isoforms transcribed from a single locus can have unlimited potential to code for diverse proteins with different functions. In this study, we explored the CTBP2/RIBEYE gene locus and its unique repertoire of transcripts that are conserved among vertebrates. We studied the transcriptional coregulator (CTBP2) and ribbon synapse-specific structural protein (RIBEYE) in the chicken retina by performing comprehensive histochemical and sequencing analyses to pinpoint cell and developmental stage-specific expression of CTBP2/RIBEYE in the developing chicken retina. We demonstrated that CTBP2 is widely expressed in retinal progenitors beginning in early retinogenesis but becomes limited to GABAergic amacrine cells in the mature retina. Inversely, RIBEYE is initially epigenetically silenced in progenitors and later expressed in photoreceptor and bipolar cells where they localize to ribbon synapses. Finally, we compared CTBP2/RIBEYE regulation in the developing human retina using a pluripotent stem cell derived retinal organoid culture system. These analyses demonstrate that similar regulation of the CTBP2/RIBEYE locus during chick and human retinal development is regulated by different members of the K50 homeodomain transcription factor family.


Stacking Domains and Dislocation Networks in Marginally Twisted Bilayers of Transition Metal Dichalcogenides.
We apply a multiscale modeling approach to study lattice reconstruction in marginally twisted bilayers of transition metal dichalcogenides (TMD). For this, we develop density functional theory parametrized interpolation formulae for interlayer adhesion energies of MoSe_{2}, WSe_{2}, MoS_{2}, and WS_{2}, combine those with elasticity theory, and analyze the bilayer lattice relaxation into mesoscale domain structures. Paying particular attention to the inversion asymmetry of TMD monolayers, we show that 3R and 2H stacking domains, separated by a network of dislocations develop for twist angles θ^{∘}<θ_{P}^{∘}∼2.5° and θ^{∘}<θ_{AP}^{∘}∼1° for, respectively, bilayers with parallel (P) and antiparallel (AP) orientation of the monolayer unit cells and suggest how the domain structures would manifest itself in local probe scanning of marginally twisted P and AP bilayers.


Genetic Burden Contributing to Extremely Low or High Bone Mineral Density in a Senior Male Population From the Osteoporotic Fractures in Men Study (MrOS).
Worldwide, one in five men aged over 50 years will experience osteoporosis or a clinical bone fracture, with a greater fracture-related mortality rate than women. However, the genetic etiology of osteoporosis in men is still poorly understood. We aimed to identify the genetic variants and candidate genes associated with extremely low or high BMD for a better understanding of the biology underlying low bone density that may point to potential therapeutic targets for increasing bone mass. Subjects from the Osteoporotic Fractures in Men Study (MrOS) cohort were evaluated by age and BMI-adjusted total hip BMD. Those with BMD values 3 SDs away from the mean were selected and the remaining individuals whose adjusted BMD ranked at the highest or lowest 100 were included. Men with the lowest adjusted BMD (N = 98) and highest adjusted BMD (N = 110) were chosen for exome sequencing. Controls (N = 82) were men of Northern and Western European descent from the US Utah population of the 1000 Genomes Project. Fisher's exact test was performed to compare low- or high-BMD subjects with controls for single-gene associations. Additionally, sets of candidate genes causative of heritable disorders of connective tissue, including osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS), were grouped for multigene and mutation burden analyses. No single-gene associations with rare variants were found for either the low BMD group (33 genes) or high BMD group (18 genes). In the group of OI genes, we detected a significant threefold increased accumulation of rare variants in low-BMD subjects compared with controls (p = 0.009). Additionally, genes associated with EDS had a twofold increased frequency in low-BMD subjects compared with controls (p = 0.03). These findings reveal a rare variant burden in OI and EDS disease genes at low BMD, which suggests a potential gene-panel approach to screen for multivariant associations in larger cohorts. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.


Antitermination in bacteriophage lambda. The structure of the N36 peptide-boxB RNA complex.
The solution structure of a 15-mer nutRboxB RNA hairpin complexed with the 36-mer N-terminal peptide of the N protein (N36) from bacteriophage lambda was determined by 2D and 3D homonuclear and heteronuclear magnetic resonance spectroscopy. These 36 amino acids include the arginine-rich motif of the N protein involved in transcriptional antitermination of phage lambda. Upon complex formation with boxB RNA, the synthetic N36 peptide binds tightly to the major groove of the boxB hairpin through hydrophobic and electrostatic interactions forming a bent alpha helix. Four nucleotides of the GAAAA pentaloop of the boxB RNA adopt a GNRA-like tetraloop fold in the complex. The formation of a GAAA tetraloop involves a loop-closing sheared base pair (G6-A10), base stacking of three adenines (A7, A8, and A10), and extrusion of one nucleotide (A9) from the loop, as observed previously for the complex of N(1-22) peptide and the nutLboxB RNA [Legault, P., Li, J., Mogridge, J., Kay, L.E. & Greenblatt, J. (1998) Cell 93, 289-299]. Stacking of the bases is extended by the indole-ring of Trp18 which also forms hydrophobic contacts to the side-chains of Leu24, Leu25, and Val26. Based on the structure of the complex, three mutant peptides were synthesized and investigated by CD and NMR spectroscopy in order to determine the role of particular residues for complex formation. These studies revealed very distinct amino-acid requirements at positions 3, 4, and 8, while replacement of Trp18 with tyrosine did not result in any gross structural changes.


Gradenigo's syndrome: successful conservative treatment in adult and paediatric patients.
A triad of retro-ocular pain, discharging ear and abducens nerve palsy, as described by Gradenigo, has been recognized for 150 years. It has traditionally been treated with surgery, but recent advances in imaging, allied with improved antibiotic treatment, allow conservative management of these cases. We present two cases of Gradenigo's syndrome: a 6-year-old child and a 70-year-old man, both without cholesteatoma, who were managed without mastoidectomy. They both had full recovery of abducens nerve function, although this took 6 and 12 weeks, respectively. In order to manage patients with Gradenigo's syndrome safely, accurate diagnostic radiology is essential, and our findings are presented and discussed. With changing medical technology, a review of the diagnostic and treatment options for this rare but serious condition, is timely.


The nasal dorsum flap.
Closure of full-thickness defects of the nasal tip and sorsum requires both a satisfactory functional and an acceptable cosmetic result. The nasal dorsum flap is particularly well suited for closure of many such defects. The basic design of the flap, as well as several useful modifications, are discussed.


Inhibition of mammalian target of rapamycin protects against reperfusion injury in diabetic heart through STAT3 signaling.
Diabetic patients suffer augmented severity of myocardial infarction. Excessive activation of the mammalian target of rapamycin (mTOR) and decreased activation of STAT3 are implicated in diabetic complications. Considering the potent cardioprotective effect of mTOR inhibitor, rapamycin, we hypothesized that reperfusion therapy with rapamycin would reduce infarct size in the diabetic hearts through STAT3 signaling. Hearts from adult male db/db or wild type (WT) C57 mice were isolated and subjected to 30 min of normothermic global ischemia and 60 min of reperfusion in Langendorff mode. Rapamycin (100 nM) was infused at the onset of reperfusion. Myocardial infarct size (IS) was significantly reduced in rapamycin-treated mice (13.3 ± 2.4 %) compared to DMSO vehicle control (35.9 ± 0.9 %) or WT mice (27.7 ± 1.1 %). Rapamycin treatment restored phosphorylation of STAT3 and enhanced AKT phosphorylation (target of mTORC2), but significantly reduced ribosomal protein S6 phosphorylation (target of mTORC1) in the diabetic heart. To determine the cause and effect relationship of STAT3 in cardioprotection, inducible cardiac-specific STAT3-deficient (MCM TG:STAT3(flox/flox)) and WT mice (MCM TG:STAT3(flox/flox)) were made diabetic by feeding high fat diet (HFD). Rapamycin given at reperfusion reduced IS in WT mice but not in STAT3-deficient mice following I/R. Moreover, cardiomyocytes isolated from HFD-fed WT mice showed resistance against necrosis (trypan blue staining) and apoptosis (TUNEL assay) when treated with rapamycin during reoxygenation following simulated ischemia. Such protection was absent in cardiomyocytes from HFD-fed STAT3-deficient mice. STAT3 signaling plays critical role in reducing IS and attenuates cardiomyocyte death following reperfusion therapy with rapamycin in diabetic heart.


[Gangrene of Fournier, treatment, classification].
The experience of treatment with favorable outcome of 3 patients, in whom gangrene of Fournier was diagnosed, was summarized.The necessity of application of "agressive" surgical tactics in early terms of the disease was stressed.


Proton imaging of siloxanes to map tissue oxygenation levels (PISTOL): a tool for quantitative tissue oximetry.
Hexamethyldisiloxane (HMDSO) has been identified as a sensitive proton NMR indicator of tissue oxygenation (pO(2)) based on spectroscopic spin-lattice relaxometry. A rapid MRI approach has now been designed, implemented, and tested. The technique, proton imaging of siloxanes to map tissue oxygenation levels (PISTOL), utilizes frequency-selective excitation of the HMDSO resonance and chemical-shift selective suppression of residual water signal to effectively eliminate water and fat signals and pulse-burst saturation recovery (1)H echo planar imaging to map T(1) of HMDSO and hence pO(2). PISTOL was used here to obtain maps of pO(2) in rat thigh muscle and Dunning prostate R3327 MAT-Lu tumor-implanted rats. Measurements were repeated to assess baseline stability and response to breathing of hyperoxic gas. Each pO(2) map was obtained in 3(1/2) min, facilitating dynamic measurements of response to oxygen intervention. Altering the inhaled gas to oxygen produced a significant increase in mean pO(2) from 55 Torr to 238 Torr in thigh muscle and a smaller, but significant, increase in mean pO(2) from 17 Torr to 78 Torr in MAT-Lu tumors. Thus, PISTOL enabled mapping of tissue pO(2) at multiple locations and dynamic changes in pO(2) in response to intervention. This new method offers a potentially valuable new tool to image pO(2) in vivo for any healthy or diseased state by (1)H MRI.


Practical overview of sexual function and advancing age.
Sexuality remains a vital aspect of human life well into advanced age. Previous sexual history, opportunity, and overall health status determine whether the sexual activity option is exercised. Normal aging is associated with some physiological changes in genital function. If elderly patients seek help for sexual problems, therapeutic interventions focus on elimination or alleviation of physical and pharmacological interferences, as well as on optimal adaptation to physiologically altered responses.


Deaths from surgical conditions in Malawi - a randomised cross-sectional Nationwide household survey.
Relatively little is known about deaths from surgical conditions in low- and middle- income African countries. The prevalence of untreated surgical conditions in Malawi has previously been estimated at 35%, with 24% of the total deaths associated with untreated surgical conditions. In this study, we wished to analyse the causes of deaths related to surgical disease in Malawi and where the deaths took place; at or outside a health facility. The study is based on data collected in a randomised multi-stage cross-sectional national household survey, which was carried out using the Surgeons Overseas Assessment of Surgical Need (SOSAS) tool. Randomisation was done on 48,233 settlements, using 55 villages from each district as data collection sites. Two to four households were randomly selected from each village. Two members from each household were interviewed. A total of 1479 households (2909 interviewees) across the whole country were visited as part of the survey. The survey data showed that in 2016, the total number of reported deaths from all causes was 616 in the 1479 households visited. Data related to cause of death were available for 558 persons (52.7% male). Surgical conditions accounted for 26.9% of these deaths. The conditions mostly associated with the 150 surgical deaths were body masses, injuries, and acute abdominal distension (24.3, 21.5 and 18.0% respectively). 12 women died from child delivery complications. Significantly more deaths from surgical conditions or injuries (55.3%) occurred outside a health facility compared to 43.6% of deaths from other medical conditions, (p = 0.0047). 82.3% of people that died sought formal health care and 12.9% visited a traditional healer additionally prior to their death. 17.7% received no health care at all. Of 150 deaths from potentially treatable surgical conditions, only 21.3% received surgical care. In Malawi, a large proportion of deaths from possible surgical conditions occur outside a health facility. Conditions associated with surgical death were body masses, acute abdominal distention and injuries. These findings indicate an urgent need for scale up of surgical services at all health care levels in Malawi.